What over When in causal agency: Causal experience prioritizes outcome prediction over temporal priority.

Prior expectations strongly structure the way we perceive the world and ourselves. For instance, action-outcome prediction can modulate time perception and causal experience. We designed a study that allowed us to investigate whether action-outcome prediction has similar effects on time perception and intentional causality. Participants viewed a stimulus that was consistent or inconsistent with the action they, or another agent executed. The stimulus preceded or followed these actions and participants reported simultaneity or causal judgments. Observers were more likely to report the consistent outcomes as being generated by the action, even when the outcomes actually preceded the action. However, outcome consistency did not modulate simultaneity judgments. These results shed insight on the relationship between time and causal experience. It suggests that time perception and causal experience do not rely in the same way on temporal information, the latter being more permeable to contextual cues such as action-outcome consistency.

Synthesis of Azocanes from Piperidines via an Azetidinium Intermediate.

α-Trifluoromethyl azocanes are accessible from 2-(trifluoropropan-2-ol) piperidines by metal-free ring-expansion involving a bicyclic azetidinium intermediate. The opening of the azetidinium intermediate was achieved by various nucleophiles (amines, alcoholates, carboxylates, phosphonates, halides and pseudo-halides) with an excellent regio- diastereo- and enantioselectivity and in good yields. The relative configuration of the piperidines and azocanes were assigned and the deprotected azocanes offer opportunities for further derivatization.

Ring-opening of azetidiniums by nucleophiles. Synthesis of polysubstituted linear amines.

This microreview focuses on the nucleophilic ring-opening of azetidiniums presenting various substitution patterns at C2, C3, and C4. In most cases, the nucleophilic ring-opening occurred in a stereoselective and regioselective fashion producing functionalized linear amines. Experimental selectivities associated with Density Functional Theory (DFT) calculations have allowed a better understanding of the parameters governing the regioselectivities.

Total Synthesis of Tiacumicin†B: Implementing Hydrogen Bond Directed Acceptor Delivery for Highly Selective ß-Glycosylations.

A total synthesis of tiacumicin B, a natural macrolide whose remarkable antibiotic properties are used to treat severe intestinal infections, is reported. The strategy is in part based on the prior synthesis of the tiacumicin B aglycone, and on the decisive use of sulfoxides as anomeric leaving groups in hydrogen-bond-mediated aglycone delivery (HAD). This new HAD variant permitted highly ß-selective rhamnosylation and noviosylation. To increase convergence, the rhamnosylated C1-C3 fragment thus obtained was anchored to the C4-C19 aglycone fragment by adapting the Suzuki-Miyaura cross-coupling used for the aglycone synthesis. Ring-size-selective macrolactonization provided a compound engaged directly in the noviolysation step with virtually total ß selectivity. The final efficient removal of all the protecting groups provided synthetic tiacumicin B.

Management of Biliary Atresia in France 1986 to 2015: Long-term Results.

OBJECTIVES: This study analyses the prognosis of biliary atresia (BA) in France since 1986, when both Kasai operation (KOp) and liver transplantation (LT) became widely available. METHODS: The charts of all patients diagnosed with BA born between 1986 and 2015 and living in France were reviewed. RESULTS: A total of 1428 patients were included; 1340 (94%) underwent KOp. Total clearance of jaundice (total bilirubin ≤20 µmol/L) was documented in 516 patients (39%). Age at KOp (median 59 days, range 6-199) was stable over time. Survival with native liver after KOp was 41%, 35%, 26%, and 22% at 5, 10, 20, and 30 years, stable in the 4 cohorts. 25-year survival with native liver was 38%, 27%, 22%, and 19% in patients operated in the first, second, third month of life or later, respectively (P = 0.0001). Center caseloads had a significant impact on results in the 1986 to 1996 cohort only. 16%, 7%, 7%, and 8% of patients died without LT in the 4 cohorts (P = 0.0001). A total of 753 patients (55%) underwent LT. Patient survival after LT was 79% at 28 years. Five-year patient survival after LT was 76%, 91%, 88%, and 92% in cohorts 1 to 4, respectively (P < 0.0001). Actual BA patient survival (from diagnosis) was 81%. Five-year BA patient survival was 72%, 88%, 87%, and 87% in cohorts 1986 to 1996, 1997 to 2002, 2003 to 2009, and 2010 to 2015, respectively (P < 0.0001). CONCLUSIONS: In France, 87% of patients with BA survive nowadays and 22% reach the age of 30 years without transplantation. Improvement of BA prognosis is mainly due to reduced mortality before LT and better outcomes after LT.

The Flash-Lag Effect as a Motion-Based Predictive Shift.

Due to its inherent neural delays, the visual system has an outdated access to sensory information about the current position of moving objects. In contrast, living organisms are remarkably able to track and intercept moving objects under a large range of challenging environmental conditions. Physiological, behavioral and psychophysical evidences strongly suggest that position coding is extrapolated using an explicit and reliable representation of object's motion but it is still unclear how these two representations interact. For instance, the so-called flash-lag effect supports the idea of a differential processing of position between moving and static objects. Although elucidating such mechanisms is crucial in our understanding of the dynamics of visual processing, a theory is still missing to explain the different facets of this visual illusion. Here, we reconsider several of the key aspects of the flash-lag effect in order to explore the role of motion upon neural coding of objects' position. First, we formalize the problem using a Bayesian modeling framework which includes a graded representation of the degree of belief about visual motion. We introduce a motion-based prediction model as a candidate explanation for the perception of coherent motion. By including the knowledge of a fixed delay, we can model the dynamics of sensory information integration by extrapolating the information acquired at previous instants in time. Next, we simulate the optimal estimation of object position with and without delay compensation and compared it with human perception under a broad range of different psychophysical conditions. Our computational study suggests that the explicit, probabilistic representation of velocity information is crucial in explaining position coding, and therefore the flash-lag effect. We discuss these theoretical results in light of the putative corrective mechanisms that can be used to cancel out the detrimental effects of neural delays and illuminate the more general question of the dynamical representation at the present time of spatial information in the visual pathways.

Study of the Construction of the Tiacumicin B Aglycone.

Our study of the synthesis of the aglycone of tiacumicin B is discussed here. We imagined two possible strategies featuring a main retrosynthetic disconnection between C13 and C14. The first strategy was based on Suzuki-Miyaura cross-coupling of 1,1-dichloro-1-alkenes, but the failure of this pathway led us to use a Pd/Cu-dual-catalyzed cross-coupling of alkynes with allenes that had never been implemented before in a total synthesis context. We used density functional theory calculations to guide our strategic choices concerning a [2.3]-Wittig rearrangement step and the final ring-size selective Yamaguchi macrolactonization. This led to two syntheses of the aglycone of tiacumicin B, with one of last generation delivering ultimately an adequately protected and glycosylation-ready aglycone.

Looking for symmetry: fixational eye movements are biased by image mirror symmetry.

Humans are highly sensitive to symmetry. During scene exploration, the area of the retina with dense light receptor coverage acquires most information from relevant locations determined by gaze fixation. We characterized patterns of fixational eye movements made by observers staring at synthetic scenes either freely (i.e., free exploration) or during a symmetry orientation discrimination task (i.e., active exploration). Stimuli could be mirror-symmetric or not. Both free and active exploration generated more saccades parallel to the axis of symmetry than along other orientations. Most saccades were small (<2°), leaving the fovea within a 4° radius of fixation. Analysis of saccade dynamics showed that the observed parallel orientation selectivity emerged within 500 ms of stimulus onset and persisted throughout the trials under both viewing conditions. Symmetry strongly distorted existing anisotropies in gaze direction in a seemingly automatic process. We argue that this bias serves a functional role in which adjusted scene sampling enhances and maintains sustained sensitivity to local spatial correlations arising from symmetry.

The relative contribution of noise and adaptation to competition during tri-stable motion perception.

Animals exploit antagonistic interactions for sensory processing and these can cause oscillations between competing states. Ambiguous sensory inputs yield such perceptual multistability. Despite numerous empirical studies using binocular rivalry or plaid pattern motion, the driving mechanisms behind the spontaneous transitions between alternatives remain unclear. In the current work, we used a tristable barber pole motion stimulus combining empirical and modeling approaches to elucidate the contributions of noise and adaptation to underlying competition. We first robustly characterized the coupling between perceptual reports of transitions and continuously recorded eye direction, identifying a critical window of 480 ms before button presses, within which both measures were most strongly correlated. Second, we identified a novel nonmonotonic relationship between stimulus contrast and average perceptual switching rate with an initially rising rate before a gentle reduction at higher contrasts. A neural fields model of the underlying dynamics introduced in previous theoretical work and incorporating noise and adaptation mechanisms was adapted, extended, and empirically validated. Noise and adaptation contributions were confirmed to dominate at the lower and higher contrasts, respectively. Model simulations, with two free parameters controlling adaptation dynamics and direction thresholds, captured the measured mean transition rates for participants. We verified the shift from noise-dominated toward adaptation-driven in both the eye direction distributions and intertransition duration statistics. This work combines modeling and empirical evidence to demonstrate the signal-strength-dependent interplay between noise and adaptation during tristability. We propose that the findings generalize beyond the barber pole stimulus case to ambiguous perception in continuous feature spaces.

Mammals Achieve Common Neural Coverage of Visual Scenes Using Distinct Sampling Behaviors.

Most vertebrates use head and eye movements to quickly change gaze orientation and sample different portions of the environment with periods of stable fixation. Visual information must be integrated across fixations to construct a complete perspective of the visual environment. In concert with this sampling strategy, neurons adapt to unchanging input to conserve energy and ensure that only novel information from each fixation is processed. We demonstrate how adaptation recovery times and saccade properties interact and thus shape spatiotemporal tradeoffs observed in the motor and visual systems of mice, cats, marmosets, macaques, and humans. These tradeoffs predict that in order to achieve similar visual coverage over time, animals with smaller receptive field sizes require faster saccade rates. Indeed, we find comparable sampling of the visual environment by neuronal populations across mammals when integrating measurements of saccadic behavior with receptive field sizes and V1 neuronal density. We propose that these mammals share a common statistically driven strategy of maintaining coverage of their visual environment over time calibrated to their respective visual system characteristics.

Dynamics of local input normalization result from balanced short- and long-range intracortical interactions in area V1.

To efficiently drive many behaviors, sensory systems have to integrate the activity of large neuronal populations within a limited time window. These populations need to rapidly achieve a robust representation of the input image, probably through canonical computations such as divisive normalization. However, little is known about the dynamics of the corticocortical interactions implementing these rapid and robust computations. Here, we measured the real-time activity of a large neuronal population in V1 using voltage-sensitive dye imaging in behaving monkeys. We found that contrast gain of the population increases over time with a time constant of ~30 ms and propagates laterally over the cortical surface. This dynamic is well accounted for by a divisive normalization achieved through a recurrent network that transiently increases in size after response onset with a slow swelling speed of 0.007-0.014 m/s, suggesting a polysynaptic intracortical origin. In the presence of a surround, this normalization pool is gradually balanced by lateral inputs propagating from distant cortical locations. This results in a centripetal propagation of surround suppression at a speed of 0.1-0.3 m/s, congruent with horizontal intracortical axons speed. We propose that a simple generalized normalization scheme can account for both the dynamical contrast response function through recurrent polysynaptic intracortical loops and for the surround suppression through long-range monosynaptic horizontal spread. Our results demonstrate that V1 achieves a rapid and robust context-dependent input normalization through a timely push-pull between local and lateral networks. We suggest that divisive normalization, a fundamental canonical computation, should be considered as a dynamic process.

Dynamic interaction between retinal and extraretinal signals in motion integration for smooth pursuit.

Due to the aperture problem, the initial direction of tracking responses to a translating bar is biased towards the direction orthogonal to the bar. This observation offers a powerful way to explore the interactions between retinal and extraretinal signals in controlling our actions. We conducted two experiments to probe these interactions by briefly (200 and 400 ms) blanking the moving target (45° or 135° tilted bar) during steady state (Experiment 1) and at different moments during the early phase of pursuit (Experiment 2). In Experiment 1, we found a marginal but statistically significant directional bias on target reappearance for all subjects in at least one blank condition (200 or 400 ms). In Experiment 2, no systematic significant directional bias was observed at target reappearance after a blank. These results suggest that the weighting of retinal and extraretinal signals is dynamically modulated during the different phases of pursuit. Based on our previous theoretical work on motion integration, we propose a new closed-loop two-stage recurrent Bayesian model where retinal and extraretinal signals are dynamically weighted based on their respective reliabilities and combined to compute the visuomotor drive. With a single free parameter, the model reproduces many aspects of smooth pursuit observed across subjects during and immediately after target blanking. It provides a new theoretical framework to understand how different signals are dynamically combined based on their relative reliability to adaptively control our actions. Overall, the model and behavioral results suggest that human subjects rely more strongly on prediction during the early phase than in the steady state phase of pursuit.

A processing work-flow for measuring erythrocytes velocity in extended vascular networks from wide field high-resolution optical imaging data.

Comprehensive information on the spatio-temporal dynamics of the vascular response is needed to underpin the signals used in hemodynamics-based functional imaging. It has recently been shown that red blood cells (RBCs) velocity and its changes can be extracted from wide-field optical imaging recordings of intrinsic absorption changes in cortex. Here, we describe a complete processing work-flow for reliable RBC velocity estimation in cortical networks. Several pre-processing steps are implemented: image co-registration, necessary to correct for small movements of the vasculature, semi-automatic image segmentation for fast and reproducible vessel selection, reconstruction of RBC trajectories patterns for each micro-vessel, and spatio-temporal filtering to enhance the desired data characteristics. The main analysis step is composed of two robust algorithms for estimating the RBCs' velocity field. Vessel diameter and its changes are also estimated, as well as local changes in backscattered light intensity. This full processing chain is implemented with a software suite that is freely distributed. The software uses efficient data management for handling the very large data sets obtained with in vivo optical imaging. It offers a complete and user-friendly graphical user interface with visualization tools for displaying and exploring data and results. A full data simulation framework is also provided in order to optimize the performances of the algorithm with respect to several characteristics of the data. We illustrate the performance of our method in three different cases of in vivo data. We first document the massive RBC speed response evoked by a spreading depression in anesthetized rat somato-sensory cortex. Second, we show the velocity response elicited by a visual stimulation in anesthetized cat visual cortex. Finally, we report, for the first time, visually-evoked RBC speed responses in an extended vascular network in awake monkey extrastriate cortex.

Motion clouds: model-based stimulus synthesis of natural-like random textures for the study of motion perception.

Choosing an appropriate set of stimuli is essential to characterize the response of a sensory system to a particular functional dimension, such as the eye movement following the motion of a visual scene. Here, we describe a framework to generate random texture movies with controlled information content, i.e., Motion Clouds. These stimuli are defined using a generative model that is based on controlled experimental parametrization. We show that Motion Clouds correspond to dense mixing of localized moving gratings with random positions. Their global envelope is similar to natural-like stimulation with an approximate full-field translation corresponding to a retinal slip. We describe the construction of these stimuli mathematically and propose an open-source Python-based implementation. Examples of the use of this framework are shown. We also propose extensions to other modalities such as color vision, touch, and audition.

Motion-based prediction is sufficient to solve the aperture problem.

In low-level sensory systems, it is still unclear how the noisy information collected locally by neurons may give rise to a coherent global percept. This is well demonstrated for the detection of motion in the aperture problem: as luminance of an elongated line is symmetrical along its axis, tangential velocity is ambiguous when measured locally. Here, we develop the hypothesis that motion-based predictive coding is sufficient to infer global motion. Our implementation is based on a context-dependent diffusion of a probabilistic representation of motion. We observe in simulations a progressive solution to the aperture problem similar to physiology and behavior. We demonstrate that this solution is the result of two underlying mechanisms. First, we demonstrate the formation of a tracking behavior favoring temporally coherent features independent of their texture. Second, we observe that incoherent features are explained away, while coherent information diffuses progressively to the global scale. Most previous models included ad hoc mechanisms such as end-stopped cells or a selection layer to track specific luminance-based features as necessary conditions to solve the aperture problem. Here, we have proved that motion-based predictive coding, as it is implemented in this functional model, is sufficient to solve the aperture problem. This solution may give insights into the role of prediction underlying a large class of sensory computations.

Speed Estimation for Visual Tracking Emerges Dynamically from Nonlinear Frequency Interactions.

Sensing the movement of fast objects within our visual environments is essential for controlling actions. It requires online estimation of motion direction and speed. We probed human speed representation using ocular tracking of stimuli of different statistics. First, we compared ocular responses to single drifting gratings (DGs) with a given set of spatiotemporal frequencies to broadband motion clouds (MCs) of matched mean frequencies. Motion energy distributions of gratings and clouds are point-like, and ellipses oriented along the constant speed axis, respectively. Sampling frequency space, MCs elicited stronger, less variable, and speed-tuned responses. DGs yielded weaker and more frequency-tuned responses. Second, we measured responses to patterns made of two or three components covering a range of orientations within Fourier space. Early tracking initiation of the patterns was best predicted by a linear combination of components before nonlinear interactions emerged to shape later dynamics. Inputs are supralinearly integrated along an iso-velocity line and sublinearly integrated away from it. A dynamical probabilistic model characterizes these interactions as an excitatory pooling along the iso-velocity line and inhibition along the orthogonal "scale" axis. Such crossed patterns of interaction would appropriately integrate or segment moving objects. This study supports the novel idea that speed estimation is better framed as a dynamic channel interaction organized along speed and scale axes.

A behavioral receptive field for ocular following in monkeys: Spatial summation and its spatial frequency tuning.

In human and non-human primates, reflexive tracking eye movements can be initiated at very short latency in response to a rapid shift of the image. Previous studies in humans have shown that only a part of the central visual field is optimal for driving ocular following responses. Herein, we have investigated spatial summation of motion information across a wide range of spatial frequencies and speeds of drifting gratings by recording short-latency ocular following responses in macaque monkeys. We show that optimal stimulus size for driving ocular responses cover a small (<20° diameter), central part of the visual field that shrinks with higher spatial frequency. This signature of linear motion integration remains invariant with speed and temporal frequency. For low and medium spatial frequencies, we found a strong suppressive influence from surround motion, evidenced by a decrease of response amplitude for stimulus sizes larger than optimal. Such suppression disappears with gratings at high frequencies. The contribution of peripheral motion was investigated by presenting grating annuli of increasing eccentricity. We observed an exponential decay of response amplitude with grating eccentricity, the decrease being faster for higher spatial frequencies. Weaker surround suppression can thus be explained by sparser eccentric inputs at high frequencies. A Difference-of-Gaussians model best renders the antagonistic contributions of peripheral and central motions. Its best-fit parameters coincide with several, well-known spatial properties of area MT neuronal populations. These results describe the mechanism by which central motion information is automatically integrated in a context-dependent manner to drive ocular responses.Significance statementOcular following is driven by visual motion at ultra-short latency in both humans and monkeys. Its dynamics reflect the properties of low-level motion integration. Here, we show that a strong center-surround suppression mechanism modulates initial eye velocity. Its spatial properties are dependent upon visual inputs' spatial frequency but are insensitive to either its temporal frequency or speed. These properties are best described with a Difference-of-Gaussian model of spatial integration. The model parameters reflect many spatial characteristics of motion sensitive neuronal populations in monkey area MT. Our results further outline the computational properties of the behavioral receptive field underpinning automatic, context-dependent motion integration.

Prevention of SARS-CoV-2 transmission during a large, live, indoor gathering (SPRING): a non-inferiority, randomised, controlled trial.

BACKGROUND: Mass indoor gatherings were banned in early 2020 to prevent the spread of SARS-CoV-2. We aimed to assess, under controlled conditions, whether infection rates among attendees at a large, indoor gathering event would be similar to those in non-attendees, given implementation of a comprehensive prevention strategy including antigen-screening within 3 days, medical mask wearing, and optimised ventilation. METHODS: The non-inferiority, prospective, open-label, randomised, controlled SPRING trial was done on attendees at a live indoor concert held in the Accor Arena on May 29, 2021 in Paris, France. Participants, aged 18-45 years, recruited via a dedicated website, had no comorbidities, COVID-19 symptoms, or recent case contact, and had had a negative rapid antigen diagnostic test within 3 days before the concert. Participants were randomly allocated in a 2:1 ratio to the experimental group (attendees) or to the control group (non-attendees). The allocation sequence was computer-generated by means of permuted blocks of sizes three, six, or nine, with no stratification. The primary outcome measure was the number of patients who were SARS-CoV-2-positive by RT-PCR test on self-collected saliva 7 days post-gathering in the per-protocol population (non-inferiority margin <0·35%). This trial is registered with ClinicalTrials.gov, NCT04872075. FINDINGS: Between May 11 and 25, 2021, 18 845 individuals registered on the dedicated website, and 10 953 were randomly selected for a pre-enrolment on-site visit. Among 6968 who kept the appointment and were screened, 6678 participants were randomly assigned (4451 were assigned to be attendees and 2227 to be non-attendees; median age 28 years; 59% women); 88% (3917) of attendees and 87% (1947) of non-attendees complied with follow-up requirements. The day 7 RT-PCR was positive for eight of the 3917 attendees (observed incidence, 0·20%; 95% CI 0·09-0·40) and three of the 1947 non-attendees (0·15%; 0·03-0·45; absolute difference, 95% CI -0·26% to 0·28%), findings that met the non-inferiority criterion for the primary endpoint. INTERPRETATION: Participation in a large, indoor, live gathering without physical distancing was not associated with increased SARS-CoV-2-transmission risk, provided a comprehensive preventive intervention was implemented. FUNDING: French Ministry of Health. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Linear model decomposition for voltage-sensitive dye imaging signals: application in awake behaving monkey.

Voltage sensitive dye imaging (VSDI) is the only technique that allows to directly measure neuronal activity over a large cortical population. It thus gives access to the dynamics of lateral interactions within or between cortical areas. However, VSDI signal suffers from a weak signal-to-noise ratio and processing methods are either rudimentary or dedicated to spatial or temporal denoising alone. Here we present an innovative method inspired by fMRI data processing, where the goal is to allow, for the first time, denoising of spatio-temporally inseparable VSDI signals and in the most challenging experimental condition, i.e. single trials in awake behaving monkeys. The method is based on a linear model (LM) decomposition of individual VSDI trials. The LM was designed meticulously by identifying all noise and signal components that are known to affect VSDI. We then compared its output against the classical methods based on blank division and detrending. LM proved to be significantly much more efficient to denoise spatial maps and temporal dynamics compared to these usual techniques. It also largely reduced trial-to-trial variability. These performances resulted in a four-fold improvement of signal-to-noise ratio and a two-fold increase of response detectability. Hence, with this method, fewer trials were needed to reach a high signal-to-noise ratio. Lastly, we showed that the LM method can accommodate for a large range of response dynamics, a crucial property for estimating spatial spread of activity or contrast dynamics. We believe that this method will make a strong contribution to imaging dynamics of population responses with high spatial and temporal resolution in trial-based experiments of awake animals.

Temporal dynamics of 2D motion integration for ocular following in macaque monkeys.

Several recent studies have shown that extracting pattern motion direction is a dynamical process where edge motion is first extracted and pattern-related information is encoded with a small time lag by MT neurons. A similar dynamics was found for human reflexive or voluntary tracking. Here, we bring an essential, but still missing, piece of information by documenting macaque ocular following responses to gratings, unikinetic plaids, and barber-poles. We found that ocular tracking was always initiated first in the grating motion direction with ultra-short latencies (approximately 55 ms). A second component was driven only 10-15 ms later, rotating tracking toward pattern motion direction. At the end the open-loop period, tracking direction was aligned with pattern motion direction (plaids) or the average of the line-ending motion directions (barber-poles). We characterized the dependency on contrast of each component. Both timing and direction of ocular following were quantitatively very consistent with the dynamics of neuronal responses reported by others. Overall, we found a remarkable consistency between neuronal dynamics and monkey behavior, advocating for a direct link between the neuronal solution of the aperture problem and primate perception and action.